HOME
How to Make Coley's Toxins
I have been asked several times how to make and use Coley's Toxins as they are no longer available. Here is the method. Although everything here is direct from Wayne Martin, who has great experience, you use it at your own risk.
HOW TO MAKE COLEY'S TOXINS
What is needed are some glassware and an incubator.
It is best to use Difco AOAC as a broth. This is a product of Difco Laboratories in Detroit. In Coley's day they started with a pound of ground beef.
Start with 1,000 cc of distilled water. Add to it 10% glucose. Then add 15 grams of Difco AOAC and 10 grams of Bacto peptone — another Difco product — and 5 grams of sodium chloride. Stir well.
Next get it to a pH of 7.1 to 7.2. This is very important. If there is no pH tester at hand, use litmus paper and get just on the alkaline side. It will most likely have a pH of about 6.8 in the beginning. The pH can be adjusted with a few drops of dilute sodium hydroxide.
Now take 100 cc of this in a small neck flask. Seed it with live streptococcus of erysipelas. Stopper it with sterile cotton – these bacteria need air but not dust. (Two labs out of the country make 500 cc at a time.)
Put in an incubator at 36 C and let grow for 10 days. It is important that the solution gets to be very cloudy.
After 10 days, take out of the incubator and get to 24 to 25 C in an air-conditioned room — and seed with live Serratia marcescens. The reason for 24 to 25 C is because the S. marcescens will not grow well at a higher temperature. Let the two grow together for 10 days at 24 to 25 C. The S. marcescens is red and the resulting solution should be pink. It is the S. marcescens that puts the punch in Coley's, so a pink solution is a good indicator.
Then sterilise by heating to 65 C for two hours. Check to see that the solution is sterile. Add 0.03 cc of benzyl alcohol per cc of solution to prevent the growth of fungus.
Store at 2 to 4 C. This vaccine will last for months at this temperature.
The cost of materials to make 1,000 cc of vaccine is about US$30.00 and this is enough to treat several hundred cancer patients.
In Coley's days, there were some very strong vaccines and some weak ones. In general a weak vaccine was just as good as a strong one. The dose just had to be greater.
ADMINISTRATION OF COLEY'S TOXINS
General
Coley's Toxins (CT) is a killed vaccine of the erysipelas streptococcus and Serratia marcescens. Where the tumour can be reached with a needle, CT is injected directly into the tumour. If this is not possible then it is administered by intramuscular or intravenous injection (iv has a greater effect). Following an injection, there should be a reaction — chills and a fever for three or more hours.
In general, the higher the fever produced the faster the remission of cancer. However, early on before anything was known about dosage, there were three cases of death from overdosing. After that, with an understanding of a proper dosage established, a great many cancer patients were treated with no problems.
If the patient normally has pain, it is often the case that there will be a high degree of pain relief, sometimes in as little as 48 hours. Patients who have pain and get relief do not mind large doses and large reactions. Patients who do not have pain often complain about big doses and big reactions.
Dosing strategy and routes of administration
In his review of 1909,[1] Coley delineated numerous aspects of the methods that he used. He found it impossible to lay down definite rules for all cases as patients' reactions, and those of their tumours, to the toxins varied considerably. As he said:
'It is very hard to lay down any definite rules as to the duration of treatment that would apply in all cases. My own feeling, based upon my experience up to the present date, is that there is much more danger in stopping the toxins too soon than in giving them too long. That they can be given for very long periods without harm is shown by some of my cases, one in particular having taken the toxins with some intervals of rest for a period of nearly four years. In many of the prominently successful cases the toxins have been give for comparatively short periods — six weeks to three or four months . . . In a few cases there has been a recurrence of the tumour after it had once disappeared under the toxins treatment, and I feel that had the toxins been given for a longer time a cure might have resulted . . . Can we, then, form any practical rules to guide us as to how long the toxins should be administered? I would say, give the toxins until the tumours have entirely disappeared, and then continue in smaller doses and greater intervals for three or four months longer. If no improvement is noted at the end of four or five weeks, a successful result is not likely to occur, and retardation of the growth is all that can be expected from a further use of the toxins. . .
'Much depends upon a judicious determination of the dosage for the given case. As a rule I like to give as much as the patient can safely stand. I always begin with one-fourth of a minim (0.015ml) diluted with sufficient boiled water to ensure accuracy of dosage, injected either into the buttocks or pectoral region. After the individual's susceptibility has been ascertained, one can inject into the tumour itself if it is in accessible region. The initial dose into the tumour should always be less, not more, than one fourth of that used elsewhere. I believe it a good plan to give the injections alternately into the tumor and into the buttocks.'
'The injections should be made deeply, whether made into the tumor or outside the limits of the same, as the local irritation is then much less than if the injections are merely made subcutaneously.' [2]
'In cases in which the tumor is situated in some region where injections are difficult or dangerous, e.g. within the abdomen or pelvis, it is better to give systemic injections, into the thighs, buttocks or abdominal wall. If the tumor becomes soft and fluctuating, it is better to open the softened areas, establish drainage and treat with moist antiseptics.[3]
'Daily injections should be given, increasing by one-fourth of a minim (0.015ml) until the desired reaction — namely a temperature of 102-104F — has been obtained. This should be modified to suit patients in a weakened condition. Having secured the desired reaction, the dose should no longer be increased until it fails to give a reaction, when it can again be increased by one-fourth to half a minim (0.015-0.03ml). The dose varies greatly with individuals; the highest dose ever given in many of the cured cases has been 7 to 10 minims (0.42- 0.6ml). On the other hand . . . [one specific case] . . . showed little improvement until large doses, as high as 30 minims (1.8ml), had been given directly into the tumor.'1
The initial elicitation of a febrile response with a given dose of the vaccine, followed by a subsequent failure to do so after repeated administration of a similar dose is reminiscent of the phenomenon of endotoxin tolerance, in association with down-regulation of cytokine production and an enhanced capacity of the reticuloendothelial system to clear the endotoxin. In his treatment, Coley repeatedly established such tolerance and then broke it by increasing the dose of vaccine. It is important to note that, in this regard, when treatment is resumed after a period of rest from it, the dose should be reduced to near the original dose as the patient will regain her original susceptibility to the vaccine.
Intravenous injections
William Coley rarely used intravenous injections. In 1929 he stated: 'I am not yet prepared to advocate intravenous injections as a routine method, nor am I prepared to say that better results may be obtained therefrom. The patients themselves much prefer them. It is a question of whether the prompt and very severe reaction to a small dose introduced intravenously is as good as or better than the delayed (for 8 hours) but more lasting moderate reaction which follows a larger dose introduced intramuscularly.
I do not think we are as yet able to answer this question.'[4] Coley's son, Bradley Coley, added in 1949: 'The dosage is of particular importance because of the violent reactions which follow an injection given into a vein. For adults in good general condition it is safe to commence with a dose of 1/80 minim (0.00075ml), while for children 1/100 (0.0006ml) is considered appropriate (in both instances diluted with saline solution up to 8-10 minims). At first the injections are given daily and the dose is increased cautiously, i.e. 1/90, 1/80, 1/70 minims, etc., as the effects of the preceding ones become less pronounced. The aim is to produce a reaction evidenced by a chill and a rise in temperature to 104F or 105F. With such a response the dose should be repeated, and increased only when a less violent effect is obtained. Thus one decides upon each successive dose only after observing the effect of the preceding one. Usually a patient can tolerate daily injections but if an unusually severe reaction is produced a day's interval of rest may be desirable.'[5]
He also said: 'The intravenous route demands hospitalization of the patient or at least constant trained nursing attention. The temperature and pulse should be recorded every hour up to eight hours after the injection or until they are found to be approaching normal levels.'
Nevertheless, the intravenous route was used until recently by Dr Don Carrow of Tampa, Florida, who was having great success treating prostate cancer patients. A patient in Alaska, a dentist with prostate cancer, had a first injection of 0.02ml which elicited a very severe reaction. He continued at 0.02ml, and as the reactions diminished the dose was increased. In May 1996 his dose was up to 0.3ml iv. Even so he felt that the reaction was less than he wanted. Throughout his treatment he continued to practise dentistry.[6] Dr Carrow is of the opinion that intramuscular injections are a waste of time.
Mineral status
Although CT has been around for a very long time and has a voluminous history, we are still learning.
In 1996 there was a 23-year old HIV+ woman in Miami who was started on 0.01ml iv. [7] (Iv injections give a bigger reaction than im.) She had such a severe reaction that it gave her doctors a big scare. The reaction was terminated with rectal suppositories of Tylenol. She was found to have severe hypotension which was due to both low potassium and low magnesium. Potassium oronate tablets sublingually restored her blood pressure to normal quickly. And a big dose of well-absorbed potassium, magnesium and calcium salts ended the problem.
In this case, mineral status was not as it should have been before treatment began; but it is thought likely that treatment with CT may result in a loss of minerals.
Before treatment, check mineral status, particularly if the patient is vegetarian, and, if low, give a mineral supplement per os. Also assume the loss of these minerals in the reaction to CT and give supplements on the day of injection.
Treatment procedure
The patient should be advised that the treatment of inoperable cancer with Coley's toxin must be extensive, that the method may be distressing and that a cure is not certain. A frank statement of the nature and severity of reactions should be made to the patient before treatment is begun. (See Physical effects below.)
CT should be diluted with saline solution for ease of use.
First test the patient's susceptibility to the treatment by systemic injections into the buttocks or pectoral region. After a few such injections, local treatment can begin.
Start with injections at a very low dose of the order of 0.01ml intravenously. This will almost certain to elicit a reaction. However, if there is no reaction, double the dose to 0.02ml. If still no reaction double again to 0.04ml and so on. The reaction to be expected is a chill followed by a fever of up to 40C (104F). The higher the fever the quicker and more lasting the remission. Once a proper dose is found, the body will develop a resistance to the vaccine and fever level will diminish. As this happens the dose will have to be increased to maintain the reaction. One reason for the low doses is to prevent the formation of necrotic tissue. This is particularly important in cases of lung and brain tumours.
If administering iv, a vein port is desirable.
The injections should be administered for four weeks, followed by one week off. Injections should then be restarted but at a lower dose — during the week's rest, the body will have lost some of its resistance to the Toxins.
Check blood pressure, pulse and temperature during the reaction. Have rectal suppositories of Tylenol on hand and terminate the reaction if blood pressure gets out of hand — it can be expected to drop slightly. Also terminate if the pulse rises above 125 or temperature rises to 40.5C (105F). If there is nausea an anti-nausea drug is indicated.
Administer injections at least 3 times per week. NOTE: Intravenous injections should not be administered on consecutive days. A good time for the injection is early morning. If the fever carries over to the next day — this is not expected to happen — do not give another injection until the temperature has returned to normal.
If the patient has fever reactions that he can manage and there are no untoward side effects there is no reason why he should not be instructed in self administering the CT. But he should be monitored regularly.
If Coley's Toxin is likely to have the desired effect, a marked improvement is usually noticed within one or two weeks, occasionally in as little as two or three days. If no improvement is seen within four to five weeks, it is likely that none will occur.2 However, there have been isolated, but noteworthy, exceptions to this rule.[8]
Drug interaction
Steroid anti-inflammatory drugs may nullify the effects of CT.
Physical effects
The reactions to Coley's toxin may not be an easy thing for a patient to tolerate. Within one hour of the injection the patient can expect to experience a shaking chill, lasting from 10 to 15 minutes, followed by a fever in the range 39C to 40C (102 to 104F). This will generally subside within 3 to 12 hours.
Treatment-related mortality was not zero. In 1917, Coley reported 6 deaths out of 1,000 cases.[9] Some were due to an embolism. In all such cases the general condition of the patient was poor. The other major cause of death was due to patients being given too high an initial dose directly into a primary vascular growth. This should not be a problem if the patient's susceptibility is tested first.
Other uncommon but potentially serious side effects include the possibility of excessive haemorrhage if the tumour has encroached upon a major blood vessel: treatment-induced necrosis of the tumour under such circumstances resulted in the loss of two patients.
Coley also reported three cases who developed a fatal nephritis which may have been due to the treatment and a fourth who was known to have died 6 years after treatment. (Nephritis is a known complication of erysipelas.)
Herpes of the lip is not uncommon but it usually disappears promptly without special treatment.
As severe reactions are often accompanied by a pronounced fall in blood pressure and a weak and rapid pulse which may persist for several hours after the chill, there is some risk in the use of toxins in elderly patients or those in advanced stages of the disease. If toxins are used under such circumstances, great caution in the selection of the initial and subsequent doses is essential.5
Supportive care
There are two obvious concerns involving the general comfort of the patient: to avoid such measures as would compromise the therapeutic effects of the treatment and to avoid subjecting the patient unnecessarily to the physical effects of the treatment. As the precise mechanism of the treatment is not known, there is some question as to what constitutes a proper balance between these two concerns. In this regard, Coley offered the following advice:
'After a chill sets in, hot water bottles and blankets should be applied. On rare occasions it may be wise to give some stimulant such as brandy . . . particularly if there is much cyanosis . . . careful attention should be paid to keeping the bowels free . . . While the patient is under the treatment the pain due to the tumor may be relieved with aspirin, codeine or morphine, administered in the usual ways.'
Supportive care for life-threatening complications includes the availability of fluid resuscitation and vasopressors for cardiovascular support. For less serious concerns, ibuprofen has been used to attenuate the constitutional effects of endotoxin administration in cancer patients[10] [11] [12] allowing for a ten-fold increase in the maximal tolerated dose, while having no obvious adverse side effects. Indomethacin has also been employed for this purpose,[13] but in another report toxicity was increased by a concurrent administration of indomethacin and repetitive administration of TNF.[14]
Until the mechanisms of the antitumour effects of Coley's toxin are fully understood, it may be better to avoid such manipulations as there is always the possibility of unexpectedly compromising the therapeutic effects of the treatment.
References
[1]. Coley W B. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the streptococcus of erysipelas and the bacillus prodigiosus). Practitioner 1909; 83: 589-613.
[2]. Coley W B. The treatment of sarcoma with the mixed toxins of erysipelas and bacillus prodigiosus. Boston Med Surg J. 1908; 158: 175-182
[3]. Coley W B. Late results of the treatment of inoperable sarcoma by the mixed toxins of erysipelas and bacillus prodigiosus. Am J Med Sci. 1906; 131: 375-430.
[4]. Coley W B. Treatment of bone sarcoma. Cancer Res. 1929; 4: 425-437.
[5]. Coley B L. Effects of bacterial products on tumors of bone. In: Neoplasms of Bone and Related Conditions — Their Etiology, Pathogenesis, Diagnosis and Treatment. Ch 58, pp 569-570. Paul B Hoeber, Inc New York, 1949.
[6]. Martin W. Personal communication. 29 May 1996.
[7]. Martin W. Personal communication. 26 May 1996.
[8]. Christian S L, Palmer L A. An apparent recovery from multiple sarcoma with involvement of both bone and soft part treated by the toxins of erysipelas and bacillus prodigiosus (Coley). Am J Surg. 1928; 4: 188-197.
[9]. Coley W B. The treatment of inoperable sarcoma with the mixed toxins of erysipelas and bacillus prodigiosus. Med Rec. 1917; 91: 966
[10]. Englehardt R, Mackensen A, Galanos C. Phase 1 trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients. Cancer Res. 1991; 51: 2524-2530.
[11]. Mackensen A, Galanos C, Engelhardt R. Modulating activity of interferon-? on endotoxin-induced cytokine production in cancer patients. Blood. 1991; 78: 3254-3258.
[12]. Pruzanski W, et al. Induction of circulating phospholipase-A2 activity by intravenous infusion of endotoxin in patients with neoplasia. J Immunother. 1992; 12: 242-246.
[13]. Lala P K, Parhar R S. Eradication of spontaneous and experimental adenocarcinoma metastases with chronic indomethacin and intermittent IL-2 therapy. Int J Cancer. 1993; 54: 677-684
[14]. Takahashi N, et al. Cycloozygenase inhibitors prevent the induction of tolerance to the toxic effects of tumor necrosis factor. J Immunother. 1993; 14: 16-21.
Related Articles
